Treatment of steroid quaternary ammonium salts



Patented Feb. 23, 1954 UNITED s-Tara's PATENT ore! TREATMENT .-.O,FSTER'GID QT-JKTEENAKY AMMDNIUM SALTS Percy IL. Julian,iMaywood,;-;andiEilwin-W.. Meyer.

.CGhicago, ,-2[ll., :assignors lto 'lThe .Glidden "Company,Oleveland,-Qhio, a corporation ofOliio No Drawing.ApplicationA-ngust23,1941,

Serial N 0. 727111336 Atclaims. 1

r-present invention relates to s. the ;:degradation of steroids, and tothe-.producticnxof :unsaturated steroids w-hichhave value for'furlthertransformation-into therapeutically active materials.

As yet :no one "has degraded 'the steroid znolcmule =via :quaternaryammonium derivatives :of tertiary flimethylamines .of th-ecyclopentanopolyhydrophenanthrene zseries. IIhe ;discovery::ofnew-methods o'fisteroid .l degradation has Ebeen "a challenge in:viewzof ."the :need for. efiicienti-m'eans tor the production oftherapeutically :activexmaterials. It has-been found that certain of thequaternary-ammonium compounds arezuseful .in steroid-degradation.

It is accordingly .anvobject of the .presentfin- =vention :to provideanew method forrth'e degradation of-the siderchainntsteroids.

Another object is to provide a process for-deragrading :the:side:chainof steroids wherein the products formed contain :new centers-ref:reactivity.

.Other :objects :willtbe :apparent :to :those skilled -int'heartr'f-romthe following description.

According :tozt-he present invention :quaternary ammonium halides I'Of:the general formula "CH3 cm I ,R vI511CH3 where R is a substitutedsaturated or unsaturated --cyclopentanopolyhydrophenanthrene 'group,and. *X I is a halogen atom selected -ifrom -the class con-s'isti-ng Iof chlorine, bromine and iodine, and the group 933 =cn; ILJH-TITICHQ XCH3 ,is attached tothe l'l-carbon atom ofithecyclo-,pentanopolyhydrophenanthrene nucleus, .are treated withsilverhydroxideor alkaline hydroxv-ides under the properconditions to yield thecorresponding quaternary ammonium hydroxides, which on heating either inthe presence .or absence of alkaline reag nts, are converted byiloss oftrimethy'l-amine and water to .20-pr.egnenes of thegeneral'formula Cl."ZGO- SBY'ES) 2 which nitrog en .wasoriginally attached. This new-double.hond afiords. an opportunity for oxidative-degradationsortheintroduction of desired .iunctionakgroupings through additionreactions xorzsuchyreactions rasiallyl halogenation.

The preparation' of the, zfi pregnenes' from the quaternar y ammoniumhalides can be accomplished..in-a varietyof ways. ,For example, theguaternaryhalide may betreated with moist silver oxide to form thequaternary ammoniumi'hydroxide which mayithenbe decomposed either bypyrolysis or heating inthe presence of alkaline reagents preferably insolution in -a "hydroxylic solvent such as 'methanol, ethanol, ethyleneglycol -or-modifiedglycols. A preferred method of preparationconsists"in -'ilissolving the quaternary halide in ethyleneg-lycolcontaining potassium "or sodium hydroxide "and heating until evolutionof trimet-hylamineneases. This method 'is commercially advantageous "inthat the quaternary -halide is--converted in one reaction stage to the Ydesired pregnene, the quaternary'hydroxide being -formed and immediatelybeing decomposed by the same reagen't.

The q-ua'ternaryammonium halides may be maderby reduetivemethylation ofthe corresponding primary amine by treatment of the latterWithiormalldehyde and form-ic ac'iclto form the Idimethylaminosteroidpand'thelatter then treated with an=organichalidesuch as an alkyl or aralkyl chl'or'ide, bromide-:or iodide.

The following examples are illustrative of the invention.

.EmampleI 2km'iirture ot3259a. of 3- acetoxy-20-amino-5-pi'egnene,i3i57:-g.- ot 590% formic acid and 35% aqueous formaldehydesolution-washeated-onthe steam= bath under-reflux forifour'h'ours. 'Themixture was then chilled, 'm-ade alkaline with dilute sod ium carbonatesolution and extracted with ether. -Theether-extractwas washed withwater several times and dried. "The white crystalline *residuenemaiiningafter "removal of solvent was f rec-rysteillizedfromether-petroleum ether (13. P.

The soformed unsaturated derivative possesses a.

- new =double' bond involving the carbon --atom' 'to crude3-acetoxy-20-dimethylamino-fi-pregnene. More er *the amine may beobtained by concentration of the mot-her liquor. The L amine -whenpurified by further recrystallization me'lts at I8435- 18755-- C.

am l

I .A solution of 17.8 g. j 'r '3-acetoxy-201dimethyl- -'sarriino tnggnene i200 cckof dryhenzene was tmated with 12 -cc. "of methyl iodide.After "re- 3 fluxing for three hours, the semi-solid mass was filteredand washed with anhydrous ether. The mother liquor was retreated with 5cc. of methyl iodide for an additional crop. There resulted 20.7 g. of3-acetoxy-5-ternorcholenyltrimethylammonium iodide, M. P. of crude,260-270 C. with decomposition.

Example III Moist silver oxide from 7.5 g. of silver nitrate was addedto a solution of 1.5 g. of 3-acetoxy-5- ternorcholenyltrimethylammoniumiodide in 50 cc. of methanol. After standing overnight, the oxide wasfiltered and washed with methanol.

The yellow filtrate was then concentrated in vacuo with the minimum ofheating. The residue of quaternary base weighed 1.0 g. This material waspyrolyzed at 210 C. and at 1 mm. pressure. After fifteen minutes at thistemperature, the residue was cooled and dissolved in ether. The ethersolution was washed with dilute hydrochloric acid followed by water. Thedried ether solution upon concentration gave a yellow gum whichcrystallized from petroleum ether (B. P. 35-60 C.). There resulted 0.2g. of crude 3-hydroxy-5, ZO-pregnene which melted at 134 C. after losingsolvent at ll3-l.l6 C.

From the hydrochloric acid washes of the ether solution there wasrecovered 0.5 g. of the hydrochloride of 3-hydroxy-20-climethylamino-5-pregnene.

Example IV A solution of 2.2 g. of 3-hydroxy-5-ternorcholenyltrimethylammonium iodide in 50 cc. of

methanol was mixed with moist silver oxide prepared from g. of silvernitrate. The mixture was then shaken for two hours, filtered and thecake washed with methanol. Nine grams of potassium hydroxide pellets wasdissolved in the filtrate and the solution was concentrated until basicvapors were evolved (volume about cc.). The solution was then-refluxedfor five hours. It was diluted with water and extracted with ether. Theethereal solution was washed with water, dilute hydrochloric acid, waterand dried.

The crystalline, white residue remaining after removal of solvent fromthe ether solution weighed 1.0 g. and melted at 136-138 C. (loss ofsolvent of crystallization at 123-126 C.). After severalrecrystallizations from methanol the pure 3-hydroxy-5, -pregnadienemelted at 138-1395 C.

Example V A solution of 3.0 g. of3-acetoxy-5-ternorcholenyltrimethylammonium iodide in cc. of methanolcontaining 10 g. of potassium hydroxide was refluxed for seven hours.After standing overnight, the reaction mixture was diluted with waterand extracted with ether. The ether extract was washed with water,dilute hydrochloric acid, water, then dried and concentrated. Thereremained 1.0 g. of a white crystalline residue which proved to be3-hydroxy -5, 20-pregnadiene.

From the hydrochloric acid washes of the ethereal solution, there wasrecovered 0.3 g. of 3-hydroxy-20-dimethylamino-5-pregnene.

In much the same fashion 3-acetoxy-5-ternorcholenyltrimethylammoniumbromide was decomposed to yield 3-hydroxy-5, 20-pregnadiene. Thequantity of product was of the same order as described in the instanceabove.

mber: A mixture of 7.2 g. of 3-acetoxy-5-ternorcholenyltrimethylammonium iodide, 15 cc. 0: water containing14. g. of potassium hydroxide pellets and 55 cc. of ethylene glycol wasrefluxed for six hours (solution temperature 130-135 C.). Slowly an oilseparated and formed an upper layer. After the reaction period, themixture was chilled andextracted with ether. The ethereal solution waswashed with water, dried and treated with enough glacial acetic acid tocause precipitation of basic material. The mixture was allowed to standin the refrigerator for a short while and filtered. By concentration ofthe clear filtrate, there resulted 2.8 g. of crude, crystalline3-hydroxy-5, ZO-pregnadiene melting at l30-l33 C. The solid which wasseparated by filtrationthe acetate of3-hydroxy-20-dimethylamino-5-pregneneweighed 1.3 g.

Example VII The acid chloride was prepared from 7.2 g. of 3(a), 12(a)-dia-cetoxy bisnor-cholanic acid and 4.2 cc. of thionyl chloride in 20cc. of dry ben- Zeno-40 cc. of dry ether. After one hour the solvent wasremoved and the acid chloride was dissolved in 130 cc. of acetone. Thissolution was treated, dropwise, at 0-5 C. with a solution of 2.3 g. ofsodium azide in 10 cc. of water. The mixture was stirred for twentyminutes and the azide was precipitated by the addition of 200 cc. ofcold water. The solid azide was separated, suspended in 130 cc. ofaqueous acetic acid and decomposed by heating to 50-60" C. for one hour.The clear solution was steam distilled, neutralized with dilute sodiumcarbonate solution and extracted with ether. The washed and dried ethersolution gave upon concentration 6.2 g. of crude 3(a),1201)-diacetoxy-ternorcholanylamine (acetamide derivative, M. P. 220-22lC.).

The crude amine was methylated by heating 5.2 g. in Sec. of formic acidand 4 cc. of 35% aqueous formaldehyde on the steam bath under reflux forfour hours. The orange liquid was poured into cold dilute sodiumhydroxide and extracted with ether. The ether solution was washed withwater, dried and concentrated in vacuo. The resulting amorphous material(5.5 g.) was crystallized from petroleum ether (B. P. 3560 C.) yieldingsmall needles of 3(a), 12(c) diacetoxy ternorcholanyldimethylaminemelting at 134-137" C.

Treatment of the ternorcholanyldimethylamine with methyl iodide inboiling benzene under refiux gave the ether insoluble, solid quaternarymethiodide.

Example VIII The crude 3(a) 12(0.)-diacetoxy-ternorcholanyldimethylammonium iodide was dissolved in amixture of 6.0 cc. of water and 30 cc. of ethylene glycol containing 6.0g. of potassium hydroxide. The mixture was re-refluxed (temperature ofboiling solution about 135 C.) for seven and onehalf hours, diluted withwater and extractedwith ether. The ether solution was then washed withwater, dilute hydrochloric acid, water and dried. Concentration of thesolution gave an amorphous residue. This was dissolved in 10 cc. ofacetic acid 3 cc. of acetic anhydride and treated with 1.0 cc. of 5 Nperchloric acid in acetic acid at ice-bath temperature and then allowedto stand for thirty minutes. Upon dilution with water, a whitecrystalline solid separated. This was filtered, washed with wateranddried 1.5 g., M. P. Several recrystallizationsfrom methanol gave largeneedle-like prisms of 3(a),

5. 12(a)-diacetoxy-20-pregnene which melted at 184-185 C.

Oxidation of this pregnene with chromic acid in acetic acid gave thecorresponding etiocholanic acid thus proving the constitution of thepregnene.

It will be appreciated that the foregoing ex amples are merelyillustrative and that many modifications may be made therein withoutdeparting from the spirit and scope of the invention. For example, inplace of the iodides, the chlorides and bromides may be used. These maybe prepared by treating the corresponding dimethyl amines with methylbromide and methyl chloride in substantially the same manner as for thepreparation of the quaternary ammonium iodides, The chlorides andbromides may then be converted to the corresponding bases in the samemanner as described for the chlorides.

Reference is made to the copending application of ourselves and anotherSerial Number 773,526, filed September 11, 1947, now Patent No.2,561,378.

Having described the invention what is claimed is:

1. The process for preparing ZO-pregnenes of the general formula RCH=CH2where R is cyclopentano 10,13 dimethylpolyhydrophenanthrene grouppossessing a double bond at the 05-06 position, which comprises treatingquaternary ammonium halides of the general formula where X is a. halogenatom selected from the class consisting of chlorine, bromine and iodineand Ris as described above, with an hydroxide selected from the classconsisting of silver hydroxwherein R has the same meaning as above.

2. The process of claim 1 in which the quaternary ammonium halides areheated in a hydroxide solvent containing dissolved alkaline hydroxide.

3. The process of claim 2 in which the hydroxylic solvent is ethyleneglycol.

'4. The process of claim 1 wherein the cyclopentanopolyhydrophenanthrenegroup of the quaternary ammonium halide has a substituent group at the3-position selected from the class consisting of hydroxyl and groupwhich yield hydroxyl upon hydrolysis.

PERCY' L. JULIAN. EDWIN W. MEYER.

Brink: Jour. Biol. Chem. 162, p. 700 (March 1946).

1. THE PROCESS FOR PREPARING 20-PREGNENES OF THE GENERAL FORMULAR-CH=CH2 WHERE R IS CYCLOPENTANO-10,13 DIMETHYLPOLYHYDROPHENANTHRENEGROUP POSSESSING A DOUBLE BOND AT THE C5-C6 POSITION, WHICH COMPRISESTREATING QUATERNARY AMMONIUM HALIDES OF THE GENERAL FORMULA